Targeting Melanoma

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A new arsenal of therapies is aimed at a widespread and lethal skin cancer.

When Edward Watson found a black spot on his left forearm in May 2004, the physician, then 39 years old, realized that it was the return of the melanoma that he had previously been treated for. This time it was beyond a skin cancer. Tumors had spread to his back, spine, adrenal gland, lung, ribs, pelvis and both hips. He took a positron emission scan, and, he says, \"I lit up like a Christmas tree.\" His surgeon told him he had eight months to live.

Watson quit his job for Pfizer (nyse: PFE - news - people ) in Australia, moved back to his native New Zealand and prepared to die. Then former Pfizer colleagues told him about a new drug, tremelimumab, in early trials. It was an antibody that primes the immune system to attack and kill tumors.

A few weeks later Watson was on a plane to the U.S. to start treatment at UCLA. The antibody produced a rash on his chest and made him lethargic. By fall he noticed that the tumor on his back was shrinking; doctors removed it and found dead cancer cells. He continued flying back quarterly to see UCLA oncologist Antoni Ribas for infusions. By June 2006 the tumors were gone. Watson remains in remission and continues to take the drug every six months. He recently started a business. \"This drug has saved my life; there are no two ways about it,\" he says.

Watson is one of the first to benefit from a new generation of melanoma drugs working their way through human trials. The drugs, in testing at Pfizer, Bristol-Myers Squibb (nyse: BMY - news - people ) and elsewhere, may improve upon medicine's dismal track record of treating the most deadly form of skin cancer. One blocks the mutant proteins inside melanoma that cause their rampant growth. Another prods the immune system into attacking and destroying the cancer. Neither approach is likely to be a cure on its own; a combination of therapies may be needed.

Melanoma, a cancer of the skin's melanocytes, or pigment cells, hits 60,000 Americans each year and kills 8,000 of them. It can strike in the prime of life and is one of the few cancers whose incidence is exploding, for unclear reasons. Risk factors include sunburn, fair skin and having lots of moles. Most cases are localized and can be cured with surgery. But when melanoma metastasizes, watch out. It \"tends to spread to many, many parts of the body at an alarming rate,\" says Memorial Sloan-Kettering Cancer Center melanoma expert Jedd D. Wolchok. Chemotherapy helps only 10% of metastatic melanoma patients, usually for just a few months.

Until recently researchers had little clue what molecular changes drive melanoma's rapid growth. But that has changed in a flurry of basic biology findings. \"In terms of understanding what makes melanoma tick, in the past five years there has been an utter revolution,\" says Keith Flaherty, a physician at the University of Pennsylvania.

In 2002 gene researchers in the U.K. discovered that two-thirds of melanomas have a mutation in a growth-promoting gene inside skin cells called BRAF. The mutation causes the BRAF protein to become stuck in the \"on\" position, so it constantly sends a signal to the nucleus that it is time to proliferate. BRAF blockers are now in early-stage human trials at Novartis (nyse: NVS - news - people ) and separately at Roche, which works with partner Plexxikon. AstraZeneca (nyse: AZN - news - people ) is in midstage trials with 180 melanoma patients for a drug that hits a related target called mitogen-activated protein kinase kinase. \"Every company I know of is interested in this,\" says Plexxikon Chief Executive Peter Hirth.

Therapies that trick the immune system into attacking melanoma are further along. Such immune system boosters have the potential to treat many types of cancer, but melanoma is one of the prime initial targets because it is one of the few cancers known to go into spontaneous remission on its own, indicating a possible immune response at work. The immune system activator interleukin-2 helps 15% of advanced melanoma cases and cures a few, but it produces such devastating side effects that patients must be hospitalized.

Pfizer's drug tremelimumab and Bristol-Myers Squibb's ipilimumab are antibodies to a protein called CTLA-4 (cytotoxic T-lymphocyte antigen-4) that acts as an emergency brake to prevent killer T cells from attacking healthy tissue. The antibodies bind to the CTLA-4, found on a cell's surface, and shut off the brake. Killer T cells then attack the cancer cells. Both drugs are in final-stage trials on hundreds of melanoma patients.

Much credit for the concept goes to immunologist James Allison, now at Sloan-Kettering in New York. In the mid-1990s he theorized that CTLA-4 might prevent the immune system from mounting an effective response against tumors. Others were skeptical. But Allison showed in 1996 that he could shrink tumors in mice by injecting them with antibodies to CTLA-4.

Both Pfizer and Medarex (nasdaq: MEDX - news - people ), a biotech firm in Princeton, New Jersey, subsequently produced human antibodies to CTLA-4 and began testing them in patients a few years later. In 2005 Bristol-Myers Squibb paid Medarex $50 million in cash plus up to $480 in payments contingent on the success of Medarex's antibody.

At a meeting of cancer specialists last June Bristol-Myers and Medarex reported their drug shrank tumors in 46, or 13%, of 356 melanoma patients. The Pfizer antibody shrank melanomas in 7 of 84 patients in a midstage trial. The success rates were modest, but cancer doctors say that some patients may have had delayed responses. In some people tumors started to regress months after they had been declared treatment failures, says Bristol-Myers Vice President Renzo Canetta.

UCLA's Ribas calls the response rates \"very low\" and cautions that the anti-CTLA-4 drugs are just a first step. But even if the drugs improve survival only minimally, they are likely to be approved, he says. Bristol-Myers and Medarex are expected to finish key trials this fall. RBC Capital Markets analyst Jason Kantor pegged the odds of disappointing results \"relatively high\" in a recent report and rated Medarex an underperform; if the response rate is under 10%, it would make near-term approval \"iffy,\" he says. Side effects of the drugs can include inflammation of the colon, thyroid or pancreas, or other autoimmune problems.

One reason for the limited response rate may be that some patients' T cells do a poor job of recognizing melanoma. To improve this situation, researchers are combining new antimelanoma vaccines with anti-CTLA-4 drugs. The idea is that the vaccines will train T cells to spot cancer, while the antibody will make sure the T cells remain activated long enough to do their dirty work.

Sharon Belvin was one of the first to try such a combination therapy. In May 2004, just a week before her wedding, she had developed a melanoma metastasis in her left lung. Belvin was only 22. The tumor grew through her chest cavity underneath her collarbone. Various chemo drugs and interleukin-2 produced nerve damage and other nasty side effects and didn't solve the problem. By June 2005 she had tumors in both lungs and could barely breathe or walk. Then Wolchok put her in a trial testing ipilimumab with an experimental Medarex vaccine. After only four treatments the tumors started to melt away. They were gone by mid-2006. The Jamesville, North Carolina resident has been off therapy for a year and is pregnant with her first child, a girl due Feb. 10.

By the Numbers
59,940 annual cases of melanoma in the U.S.
8,110 annual deaths.
99% five-year survival rate, localized disease.
15% five-year survival rate, widespread disease.

Source: American Cancer Society.

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